Pre-emptive Diclectin therapy for the management of nausea and … · 2018-07-03 · Pre-emptive Diclectin® therapy for the management of nausea and vomiting of pregnancy and hyperemesis

Pre-emptive Diclectin® therapy for the management of

nausea and vomiting of pregnancy and hyperemesis gravidarum

Caroline Maltepe and Gideon Koren MD

September 5th, 2013

National Pregnancy Sickness Support Conference, London

Disclosure

This study was funded by Duchesnay® Inc.

Nausea and Vomiting of Pregnancy (NVP)

• Up to 85% of pregnant women until 12-16 wks• 20% will experience symptoms until time of

delivery

• NVP symptoms (mild to severe)• Begin between 4 – 9 wks gestation• Peak between 7 – 12 wks gestation

• Hyperemesis gravidarum (HG)• Up to 2% of pregnant women• High recurrence rate (75-85%) of severe NVP/HG

Impact of NVP• Physical

• Dehydration and weight loss• Hospitalization(s)• Termination of pregnancy• Maternal/fetal complications

• Psychological• Affecting home and social life• Depression/anxiety, frustration and helplessness• Time loss from work• Anxiety and fear for future pregnancy(ies)

• Financial• High direct and indirect costs of NVP

Pre-emptive treatment of nausea and vomiting

• Prophylactic (pre-emptive) antiemetic treatment

• Cancer chemotherapy1

• Motion sickness2

• Cyclic vomiting3

1Mattiuzzi et al. Cancer 20102Gil et al. Clin Neuropharm 20123Hejazi and McCallum. Alim Pharm Ther

2011

• Prospective, non randomized study on pre-emptive use of any antiemetic treatment for severe NVP and HG4

4Koren and Maltepe. J Obstet Gynaecol. 2004

Pre-emptive therapy for NVP

• A 2004 prospective, non randomized study• Study group: 25 women with a previous history of severe NVP or HG

called when planning or early pregnancy with no symptoms of NVP

• Control group: 35 women with a previous history of severe NVP or HG called with NVP symptoms

• Study group counseled to start any antiemetic drug when aware of pregnancy before NVP symptoms or on first sign of NVP

• Study demonstrated:• Lower incidence of HG compared to previous pregnancy (P=0.01)

• Starting any antiemetic therapy prior to or at onset of NVP reduced the severity of symptoms (P=0.01)

• Continuous and individualized counseling very beneficial

Koren G and Maltepe C.2004 J Obstet Gynaecol

Diclectin ®

Delayed release Doxylamine succinate 10mg/Pyridoxine 10mg

• The only drug labelled for pregnancy use in Canada• First line therapy for NVP (SOGC, ACOG &APGO) 4

• Many studies including two meta-analyses have confirmed its safety1,2,3,4

• Standard dose up to 4 tabs/day. However, safety up to 12 tabs/day1

• Not associated with any long term effects on neurodevelopment2

1Atanachkovic,G et al.2001 J Clin Pharmacol. Aug;41(8):842-52 Nulman I et al. 2009 J Pediatr. 155, 45-50 3 Bishai R. et al. 2000 Can J Clin Pharmacol. Autumn;7(3):138-43.4 APGO 2011 Monograph Educational series on women’s health issues on nausea and vomiting of pregnancy

Study objectives

1. To determine the effectiveness of pre-emptive use of

Diclectin® during pregnancy before the onset of

NVP symptoms in women who are at a high risk for

recurrence of severe NVP or HG

2. To compare this with the effects of Diclectin®

started at the onset of NVP symptoms in a similar

history of NVP

Prospective, randomized, open-label pre-emptive Diclectin® study

Patient recruitmentNVP Helpline(2005-2012)

Blinded randomization

Methods

INITIAL CALL

Motherisk NVP Helpline 1-800-436-8477

•Personal data (demographic)•Medical and obstetric history•Medication and vitamin use•NVP severity assessment: PUQE, WB, self report•Detailed symptom assessment

• Evidence-based information• Pharmacological and non-

pharmacological approaches• Dietary and lifestyle changes

•Depending on severity of NVP•Scheduled by the NVP counselor or initiated by patients.

Methods cont’d

Einarson A et al. 2007 Can Fam Phys

Motherisk NVP algorithm

Validated PUQE-24hrs Scoring System(Pregnancy Unique Quantification of Emesis)

How many hours in past 24 hrs had you felt nauseated/sick to stomach?

None(1)

1 hr or less(2)

2-3 hrs(3)

4-6 hrs(4)

> 6 hrs(5)

How many times in the past 24 hrs did you vomit?

≥ 7 times(5)

5-6 times(4)

3-4 times(3)

1-2 times(2)

None(1)

How many times in the past 24 hrs did you experience gagging or retching or dry heaves?

None(1)

1-2 times(2)

3-4 times(3)

5-6 times(4)

≥ 7 times(5)

Mild: 3-6 Moderate: 7-12 Severe: ≥13

On a scale of 0-10 how would you rate your overall Well-Being (WB)?0 (Worst possible)_________10 (The best you felt before pregnancy)

Ebrahimi N et al. 2009, J Obstet Gynaecol Can

Methods cont’d

How many hours have you slept out of 24 hours? Why?____________________

• Both pre-emptive and control groups started with 2 tablets of Diclectin® at bedtime with gradual increase of their dose according to symptom escalation

• Both pre-emptive and control groups were continuously followed up and received intensive protocolized counseling

• PUQE-24 and WB scores were used at enrolment and each follow up to measure the severity of NVP

Methods cont’d

Results

• Significant reduction of HG with pre-emptive Diclectin ® treatment (43% the pre-emptive group vs 17% the control group)

• 70% reduction of cases with moderate-severe NVP (PUQE≥11) in the 3 first weeks of NVP in the pre-emptive group (p<0.04)

• Significant negative correlation between peak PUQE and Well-Being (WB) scores

• Earlier resolution of NVP symptoms in the pre-emptive group (Mean GA of 26 wks vs 33 wks for control group)

• Both study groups had similar:• Demographic characteristics

(Age, BMI, history of severe NVP/HG, ect)

• Mean Diclectin® dose (range 2-9 tablets)

• Mean of 8 follow-up calls/counseling

Comparison of effectiveness between the two arms

Pre-emptive (n=30) Control (n=29) P

Rates (%) of PUQE ≥11 in first 4 (15%) (n=26) 9 (39%) (n=23) <0.04

3 weeks of NVP 

NVP resolved before labor 18/23 (78%) 11/22 (50%) <0.002

Resolution of NVP 26 33 0.18

 (median weeks)

Distribution of HG in previous vs. present pregnancy

HG in previous pregnancy 19 (63%) 11 (38%) 0.047

HG in present pregnancy 6 (20%) 6 (17%)

Study characteristics of the women in both groups Pre-emptive (n=30) Control (n=29) P

Mean age-yr (SD) 32.2(4.7) 31.3(3.2) 0.37

BMI (SD) 25.2(5.7) 27.3(6.6) 0.2

Mean daily dose of Diclectin®

(mg/ kg) (SD) 0.65(0.23) 0.56(0.24) 0.2

Mean gestational age (in weeks)

when NVP symptoms began (SD) 5.30( 1.02) 5.45(1.88)

Mean start of pre-emptive therapy (SD) 3.8(0.98)

Some associated medical conditions

Motion sickness 7 4 N.S.

Acid Reflux/Indigestion 23 27 N.S.

Depression/Anxiety 8 16 0.04

Low iron/anemia 15 9 N.S.

Headaches/Migraines 5 17 0.01

HG in previous pregnancy 19 11 0.07

Conclusions

• Pre-emptive Diclectin® treatment prevents severe NVP from recurring in a subsequent pregnancy

• Reduces symptoms by implementing:• Dietary and lifestyles strategies

• Non-pharmacological and pharmacological approaches

• Improves maternal quality of life

Study impact

Prevent maternal and fetal complications

Reduce the need for enteral and parenteral therapy and their associated risks

Reduce the costs associated with severe

NVP/HGTime loss of work

Hospitalization

Thank you

PUQE and WB correlation

• Significant negative correlation between peak PUQE score and Well-Being (WB) score among participants.

• Women with PUQE of 13-15 had a median WB score of 1.5/10

• Women with PUQE of 7-12 had a median WB score of 5/10

• Women with PUQE of 3-6 had a median WB score of 7.5/10

Pre-emptive therapy for NVP

Results

Koren G and Maltepe C.2004 J Obstet Gynaecol